Focal Adhesion Kinase: A Key Mediator of Transforming Growth Factor Beta Signaling in Fibroblasts

Leask, Andrew

doi:10.1089/wound.2012.0363

Cited by 44 publications

(42 citation statements)

References 15 publications

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“…Because FAK signaling is implicated in myofibroblast transdifferentiation and activation [42],[43], we compared FAK activity between HT and LT cells. Western blotting for p-FAK and immunofluorescence demonstrated that HT cells had abundant expression of p-FAK in the presence or absence of TGF-b1.…”

Section: Resultsmentioning

confidence: 99%

The role of α-smooth muscle actin in fibroblast-mediated matrix contraction and remodeling

Shinde

Humeres

Frangogiannis

2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

381

257

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Cardiac myofibroblasts play an important role in myocardial remodeling. Although α-smooth muscle actin (α-SMA) expression is the hallmark of mature myofibroblasts, its role in regulating fibroblast function remains poorly understood. We explore the effects of the matrix environment in modulating cardiac fibroblast phenotype, and we investigate the role of α-SMA in fibroblast function using loss- and gain-of-function approaches. In murine myocardial infarction, infiltration of the infarct border zone with abundant α-SMA-positive myofibroblasts was associated with scar contraction. Isolated cardiac fibroblasts cultured in plates showed high α-SMA expression localized in stress fibers, exhibited activation of focal adhesion kinase (FAK), and synthesized large amounts of extracellular matrix proteins. In contrast, when these cells were cultured in collagen lattices, they exhibited marked reduction of α-SMA expression, negligible FAK activation, attenuated collagen synthesis, and increased transcription of genes associated with matrix metabolism. Transforming Growth Factor-βl-mediated contraction of fibroblast-populated collagen pads was associated with accentuated α-SMA synthesis. In contrast, serum- and basic Fibroblast Growth Factor-induced collagen pad contraction was associated with reduced α-SMA expression. α-SMA siRNA knockdown attenuated contraction of collagen pads populated with serum-stimulated cells. Surprisingly, α-SMA overexpression also reduced collagen pad contraction, suggesting that α-SMA is not sufficient to promote contraction of the matrix. Reduced contraction by α-SMA-overexpressing cells was associated with attenuated proliferative activity, in the absence of any effects on apoptosis. α-SMA may be implicated in contraction and remodeling of the extracellular matrix, but is not sufficient to induce contraction. α-SMA expression may modulate cellular functions, beyond its effects on contractility.

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Section: Resultsmentioning

confidence: 99%

The role of α-smooth muscle actin in fibroblast-mediated matrix contraction and remodeling

Shinde

Humeres

Frangogiannis

2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

381

257

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“…[48][49][50] In our study, rough Ti (grade 3) inhibited FAK phosphorylation of HCF at 1.5 months in the absence of TGFb1. According to proposed FAK signaling pathways, 51 FAK mediates TGFb1 signaling, which in turn activates a-SMA expression and promotes collagen deposition by myofibroblasts. In presence of TGFb1 stimulation in culture media, FAK phosphorylation was not affected by Ti surface topography.…”

Section: Discussionmentioning

confidence: 99%

The Role of Titanium Surface Microtopography on Adhesion, Proliferation, Transformation, and Matrix Deposition of Corneal Cells

Zhou

Lei

Chodosh

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Titanium (Ti) is an excellent implantable biomaterial that can be further enhanced by surface topography optimization. Despite numerous data from orthopedics and dentistry, the effect of Ti surface topography on ocular cells is still poorly understood. In light of the recent adaptation of Ti in the Boston Keratoprosthesis artificial cornea, we attempted to perform an extended evaluation of the effect of Ti surface topography on corneal cell adhesion, proliferation, cytotoxicity, transformation, and matrix deposition.METHODS. Different surface topographies were generated on medical grade Ti-6Al-4V-ELI (extra-low interstitial), with linearly increased roughness (polished to grit blasted). Biological response was evaluated in vitro using human corneal limbal epithelial (HCLE) cells, stromal fibroblasts (HCF), and endothelial cells (HCEnC). RESULTS.None of the Ti surface topographies caused cytotoxicity to any of the three corneal cell types. However, rough Ti surface inhibited HCLE and HCF cell adhesion and proliferation, while HCEnC proliferation was unaffected. Long-term experiments with HCF revealed that rough Ti surface with R a (the arithmetic average of the profile height from the mean line) ‡ 1.15 lm suppressed HCF focal adhesion kinase phosphorylation, changed fibroblast morphology, and caused less aligned and reduced deposition of collagen matrix as compared to smooth Ti (R a 0.08 lm). In the presence of transforming growth factor b1 (TGFb1) stimulation, rough Ti inhibited alpha-smooth muscle actin (a-SMA) expression and collagen deposition, leading to decreased myofibroblast transformation and disorganization of the collagen fibrils as compared to smooth Ti.CONCLUSIONS. This study suggests that Ti surface topography regulates corneal cell behavior in a tissue-dependent manner that varies across the corneal strata. Contrary to the accepted paradigm, smooth surface topography can enhance cell adhesion and proliferation and increase matrix deposition by corneal cells.

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“…They also proved that FAK deficiency impaired myofibroblast differentiation [164]. FAK has been shown to be a key mediator of TGFβ signaling in lung and skin fibroblasts [165, 166]. …”

Section: End Effectors Of the Fibrotic Processmentioning

confidence: 99%

Integrins and integrin-related proteins in cardiac fibrosis

Chen

Ross

et al. 2016

Journal of Molecular and Cellular Cardiology

128

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Cardiac fibrosis is one of the major components of the healing mechanism following any injury of the heart and as such may contribute to both systolic and diastolic dysfunction in a range of pathophysiologic conditions. Canonically, it can occur as part of the remodeling process that occurs following myocardial infarction or that follows as a response to pressure overload. Integrins are cell surface receptors which act in both cellular adhesion and signaling. Most importantly, in the context of the continuously contracting myocardium, they are recognized as mechanotransducers. They have been implicated in the development of fibrosis in several organs, including the heart. This review will focus on the involvement of integrins and integrin-related proteins, in cardiac fibrosis, outlining the roles of these proteins in the fibrotic responses in specific cardiac pathologies, discuss some of the common end effectors (Angiotensin II, transforming growth factor beta 1 and mechanical stress) through which integrins function and finally discuss how manipulation of this set of proteins may lead to new treatments which could prove useful to alter the deleterious effects of cardiac fibrosis.

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Focal Adhesion Kinase: A Key Mediator of Transforming Growth Factor Beta Signaling in Fibroblasts

Cited by 44 publications

References 15 publications

The role of α-smooth muscle actin in fibroblast-mediated matrix contraction and remodeling

The role of α-smooth muscle actin in fibroblast-mediated matrix contraction and remodeling

The Role of Titanium Surface Microtopography on Adhesion, Proliferation, Transformation, and Matrix Deposition of Corneal Cells

Integrins and integrin-related proteins in cardiac fibrosis

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